L-asparaginase inhibits invasive and angiogenic activity and induces autophagy in ovarian cancer

Riccardo Alessandro, Elise C. Kohn, Victoria Virador, Alyssa Perroy, Amanda Walker, Ryan Henning, Geoffrey Kim, Minshu Yu

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Abstract

AbstractRecent work identified L-asparaginase (L-ASP) as a putative therapeutic target for ovarian cancer. We suggest that L-ASP, a dysregulator of glycosylation, would interrupt the local microenvironment, affecting the ovarian cancer cell—endothelial cell interaction and thus angiogenesis without cytotoxic effects. Ovarian cancer cell lines and human microvascular endothelial cells (HMVEC) were exposed to L-ASP at physiologically attainable concentrations and subjected to analyses of endothelial tube formation, invasion, adhesion and the assessment of sialylated proteins involved in matrix-associated and heterotypic cell adhesion. Marked reduction in HMVEC tube formation in vitro, HMVEC and ovarian cancer cell invasion, and heterotypic cell-cell and cell-matrix adhesion was observed (P < 0.05–0.0001). These effects were associated with reduced binding to ß1integrin, activation of FAK, and cell surface sialyl LewisX (sLex) expression. No reduction in HMVEC E-selectin expression was seen consistent with the unidirectional inhibitory actions observed. L-ASP concentrations were non-toxic to either ovarian cancer or HMVEC lines in the time frame of the assays. However, early changes of autophagy were observed in both cell types with induction of ATG12, beclin-1, and cleavage of LC-3, indicating cell injury did occur. These data and the known mechanism of action of L-ASP on glycosylation of nascent proteins suggest that L-ASP reduces of ovarian cancer dissemination and progression through modification of its microenvironment.The reduction of ovarian cancer cell surface sLex inhibits interaction with HMVEC and thus HMVEC differentiation into tubes, inhibits interaction
Lingua originaleEnglish
pagine (da-a)2369-2378
Numero di pagine10
RivistaJournal of Cellular and Molecular Medicine
VolumeVol 16
Stato di pubblicazionePublished - 2012

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All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Cell Biology

Cita questo

Alessandro, R., Kohn, E. C., Virador, V., Perroy, A., Walker, A., Henning, R., Kim, G., & Yu, M. (2012). L-asparaginase inhibits invasive and angiogenic activity and induces autophagy in ovarian cancer. Journal of Cellular and Molecular Medicine, Vol 16, 2369-2378.